Synthesis Of Trifluoromethylquinoline Derivatives Via Copper-Catalyzed Cascade Cyclization Reaction

Quinolines represent an important class of biologically active natural products which have been widely employed as privileged structures for developing pharmaceutically important molecules. In particular, trifluoromethylated quinolines are particularly attractive because introducing fluorine atoms into an organic substrate sometimes play a pivotal role in its physical, chemical, and biological properties. Due to the importance of these heterocycles, efficient synthetic methods to trifluoromethylated quinolines have already emerged. However, efficient synthetic methods for securing trifluoromethylated quinolines remains of vital importance because there are still some shortcomings, such as harsh reaction conditions and the use of expensive catalysts. Therefore, the development of a new practical process for the synthesis of trifluoromethylated quinolines under mild conditions is desirable.The thesis includes the following three aspects.1. The recently synthetic development of trifluoromethylation reaction via using trifluoromethyl-containing building-block and various trifluoromethylation reagents was reviewed.2. Then, we described the Cu Cl2/air-promoted cyclization/oxidation of N-(2-alkenylaryl) enamines via using trifluoromethyl-containing building-block,which provides a novel and efficient route to 2-(trifluoromethyl)quinoline derivatives with good functional group tolerance. Adjusting the reaction conditions, we could selectively synthesize with or without 4-alkyl substituted 2-(trifluoromethyl)quinoline derivatives.3. The trifluoromethylation of 2-(2-ethynylphenylamino)maleate for the synthesis of trifluoromethyl-containing quinoline derivatives was achieved using Togni's reagent as trifluoromethyl source under the catalyzed by Cu2 O in the presence of pyridine(3.0 equiv). A wide range of target products were obtained in moderate to good yields. On the basis of previous reports and experimental study, we proposed a plausible mechanism, which involves a cascade of trifluoromethyl radical addition and the subsequent cyclization sequence.